Restoring neuronal progranulin reverses deficits in a mouse model of frontotemporal dementia

Brain. 2017 May 1;140(5):1447-1465. doi: 10.1093/brain/awx060.

Abstract

Loss-of-function mutations in progranulin (GRN), a secreted glycoprotein expressed by neurons and microglia, are a common autosomal dominant cause of frontotemporal dementia, a neurodegenerative disease commonly characterized by disrupted social and emotional behaviour. GRN mutations are thought to cause frontotemporal dementia through progranulin haploinsufficiency, therefore, boosting progranulin expression from the intact allele is a rational treatment strategy. However, this approach has not been tested in an animal model of frontotemporal dementia and it is unclear if boosting progranulin could correct pre-existing deficits. Here, we show that adeno-associated virus-driven expression of progranulin in the medial prefrontal cortex reverses social dominance deficits in Grn+/- mice, an animal model of frontotemporal dementia due to GRN mutations. Adeno-associated virus-progranulin also corrected lysosomal abnormalities in Grn+/- mice. The adeno-associated virus-progranulin vector only transduced neurons, suggesting that restoring neuronal progranulin is sufficient to correct deficits in Grn+/- mice. To further test the role of neuronal progranulin in the development of frontotemporal dementia-related deficits, we generated two neuronal progranulin-deficient mouse lines using CaMKII-Cre and Nestin-Cre. Measuring progranulin levels in these lines indicated that most brain progranulin is derived from neurons. Both neuronal progranulin-deficient lines developed social dominance deficits similar to those in global Grn+/- mice, showing that neuronal progranulin deficiency is sufficient to disrupt social behaviour. These data support the concept of progranulin-boosting therapies for frontotemporal dementia and highlight an important role for neuron-derived progranulin in maintaining normal social function.

Keywords: FTD; dementia; experimental models; gene therapy; progranulin.

MeSH terms

  • Animals
  • Calcium-Calmodulin-Dependent Protein Kinase Type 2 / genetics
  • Conditioning, Psychological
  • Dependovirus
  • Disease Models, Animal
  • Female
  • Frontotemporal Dementia / genetics
  • Frontotemporal Dementia / metabolism*
  • Frontotemporal Dementia / therapy*
  • Genetic Vectors
  • Granulins
  • Intercellular Signaling Peptides and Proteins / deficiency
  • Intercellular Signaling Peptides and Proteins / genetics
  • Intercellular Signaling Peptides and Proteins / metabolism*
  • Male
  • Maze Learning
  • Mice
  • Mice, Knockout
  • Mice, Transgenic
  • Nestin / genetics
  • Neurons / metabolism*
  • Prefrontal Cortex / metabolism
  • Social Behavior
  • Social Dominance

Substances

  • Granulins
  • Grn protein, mouse
  • Intercellular Signaling Peptides and Proteins
  • Nestin
  • Calcium-Calmodulin-Dependent Protein Kinase Type 2